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    Summary
    EudraCT Number:2016-004446-29
    Sponsor's Protocol Code Number:LIBERAL-Trial
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-03-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2016-004446-29
    A.3Full title of the trial
    Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients
    A.3.2Name or abbreviated title of the trial where available
    LIBERAL-Trial
    A.4.1Sponsor's protocol code numberLIBERAL-Trial
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital Wuerzburg, Institution under public law, represented by the Medical Director
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGerman Research Foundation
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Wuerzburg, Department of Anaesthesiology
    B.5.2Functional name of contact pointPatrick Meybohm
    B.5.3 Address:
    B.5.3.1Street AddressOberduerrbacher Str. 6
    B.5.3.2Town/ cityWuerzburg
    B.5.3.3Post code97080
    B.5.3.4CountryGermany
    B.5.6E-mailmeybohm_p@ukw.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRed Blood Cell Concentrate
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRED BLOOD CELLS
    D.3.9.3Other descriptive nameRed Blood Cell Concentrates (RBCs)
    D.3.9.4EV Substance CodeSUB15114MIG
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeRed Blood Cell Concentrate
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRed Blood Cell Concentrate
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRED BLOOD CELLS
    D.3.9.3Other descriptive nameRed Blood Cell Concentrates (RBCs)
    D.3.9.4EV Substance CodeSUB15114MIG
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Elderly patients (>= 70 years) undergoing intermediate- or high-risk non-cardiac surgery
    E.1.1.1Medical condition in easily understood language
    postoperative anaemia in elderly patients
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 27.0
    E.1.2Level PT
    E.1.2Classification code 10048861
    E.1.2Term Anaemia postoperative
    E.1.2System Organ Class 10022117 - Injury, poisoning and procedural complications
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate if in a geriatric population, a liberal strategy reduces the occurrence of major adverse events after non-cardiac surgery compared to a restrictive transfusion strategy within 90 days after surgery.
    The primary efficacy outcome is defined as a composite of:
    I. All-cause mortality defined as death from any cause
    II. Acute myocardial infarction confirmed by cardiologist
    III. Acute ischaemic stroke confirmed by neurologist
    IV. Acute kidney injury (stage III) defined according to the Kidney Disease Improving Global Outcomes criteria: Increase plasma creatinine level >= 3 times within 7 days or initiation of RRT
    V. Acute mesenteric ischaemia (ischaemia confirmed by intervention)
    VI. Acute peripheral vascular ischaemia defined as a new non-thrombotic compromised circulation in a limb confirmed by angiography and/or leading to surgery
    After hospital discharge, events of composite outcome will only be considered as present if they lead to hospital re-admission or death.
    E.2.2Secondary objectives of the trial
    Liberal transfusion strategy:
    - reduces occurrence of any individual component of the composite of primary objectives at discharge and 90 days and 1 year after surgery
    - results in shorter total hospital stay and shorter LOS on ICU, improves functional status and health-related quality of life at 90 days after surgery
    - reduces the occurrence of acute kidney injury stage I-II defined according to the Kidney Disease Improving Global Outcomes criteria during the initial hospital stay
    - reduces Re-hospitalisation rate within 90 days after surgery
    - does not increase occurrence of infections requiring therapeutic intravenous antibiotic treatment (pneumonia, wound infection, sepsis, central line associated blood stream infection) during the initial hospital stay or leading to hospital re-admission within 90 days after surgery.

    In addition, the proportion of patients receiving RBC transfusion and the number of units transfused are evaluated.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria for Registration (Step I)
    1. Elderly patients (>= 70 years)
    2. Undergoing intermediate- or high-risk non-cardiac surgery (according to the ESC/ESA Guidelines: surgery-related risk of cardiovascular death and myocardial infarction)
    a. Intermediate risk (30-day risk 1-5%): e.g., intraperitoneal (splenectomy, hiatal hernia), peripheral arterial angioplasty, endovascular aneurysm repair, head and neck, major neurological/orthopaedic (hip and spine), major urological, major gynaecological, intra-thoracic surgery
    b. High-risk (30-day risk > 5%): e.g., aortic and major vascular, open limb revascularisation, (partial) duodeno-pancreatic, (partial) liver resection, oesophagectomy, adrenal or (partial or radical) renal resection, total cystectomy
    3. Written informed consent; obtained before surgery from the patients or from their legally authorised representative (authorisation including clinical research/clinical trials) / legal guardian, if the patient is unable to provide informed consent.

    Inclusion Criteria for Randomisation (Step II)
    Registered patients will be randomised only if and as soon as Hb falls <= 9 g/dl (in spite of possible autologous transfusion) during surgery (=day 0) or day 1, 2, or 3 after surgery. If Hb remains > 9 g/dl (even after a two-stage surgery) patient does not enter the main study but vital status (all-cause mortality) will be determined 90 days after surgery
    E.4Principal exclusion criteria
    Exclusion Criteria for Registration (Step I)
    1. preoperative Hb level <= 9 g/dl
    2. chronic kidney disease requiring dialysis
    3. suspected lack of compliance with follow-up procedures
    4. participation in other interventional trials
    5. expected death within 3 months
    6. inability to provide informed consent with absence of a legally authorised representative/ legal guardian
    7. temporary inability to provide informed consent
    8. previous participation in our trial
    9. Patients who are prevented from having blood and blood products according to a system of beliefs (e.g. Jehovah’s Witnesses)
    10. preoperative autologous blood donation

    Exclusion Criteria for Randomisation (Step II)
    1. Occurrence of any component of composite endpoint after registration:
    - Acute myocardial infarction
    - Acute ischaemic stroke
    - Acute kidney injury (stage III)
    - Acute mesenteric ischaemia
    - Acute peripheral vascular ischaemia
    2. Any allogeneic blood transfusion after registration
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy outcome is defined as a composite of (within 90 days after surgery):
    I. All-cause mortality is defined as death from any cause.
    II. Acute myocardial infarction confirmed by a cardiologist.
    III. Acute ischaemic stroke confirmed by a neurologist.
    IV. Acute kidney injury (stage III) is defined according to the Kidney Disease Improving Global Outcomes criteria: Increase of plasma creatinine level >= 3 times within a time window of 7 days or initiation of renal replacement therapy. (Serum creatinine concentration will be measured at least every 7 days until hospital discharge. Urine output criteria will not be used to define acute kidney injury because most of hospital do not mandate hourly urine output measurements on all patients, and because of the likelihood of inaccurate measurement in the substantial number of patients without urinary catheters.)
    V. Acute mesenteric ischaemia is defined as ischaemia confirmed by intervention (abdominal surgery or mesenteric angiography).
    VI. Acute peripheral vascular ischaemia is defined as a new non-thrombotic compromised circulation in a limb confirmed by angiography and/or leading to surgery.

    After hospital discharge, events will only be considered as present if they lead to hospital re-admission or death. Direct transfer to another hospital will not be defined as re-admission. Hospital re-admission requires at least one overnight stay in an acute hospital.
    An ambulatory hospital visit or an admission to a rehabilitation facility or day hospital is not regarded as hospital readmission.

    After hospital discharge, the composite endpoint will be assessed by a telephone interview. In cases of inability to follow by telephone, the primary endpoint will be ascertained from participant’s family doctor, or hospital files, respectively.
    E.5.1.1Timepoint(s) of evaluation of this end point
    90 days after surgery
    E.5.2Secondary end point(s)
    Secondary outcome measures are the following:
    - The occurrence of any individual component of the composite of all-cause mortality, acute myocardial infarction, acute stroke, acute kidney injury stage III, acute mesenteric ischaemia, and/or acute peripheral vascular ischaemia at hospital discharge, at 90 days, and 1 year after surgery.
    - The occurrence of any ischaemic event, i.e., acute myocardial infarction, acute stroke, acute kidney injury stage III, acute mesenteric ischaemia, and/or acute peripheral vascular ischaemia at hospital discharge, at 90 days, and 1 year after surgery, treating all-cause mortality as competing risk.
    - Proportion of patients receiving RBC transfusion and the number of units transfused.
    - Total length of stay in the intensive care unit and in hospital from randomisation to discharge (for strategy comparison); in addition, total length of stay in the intensive care unit and in hospital from admission to discharge will be used for descriptive purposes.
    - The occurrence of acute kidney injury (stage I or II) defined according to the Kidney Disease Improving Global Outcomes criteria (stage I: increase of plasma creatinine level >= 1.5-1.9 times baseline or >= 0.3mg/dl within 48 hours; stage II: increase of plasma creatinine level >= 2-2.9 times baseline within a time window of 7 days) during the initial hospital stay
    - Time to (first) infection (infection requiring therapeutic intravenous antibiotic treatment (pneumonia, wound infection, sepsis, central line associated blood stream infection)) during the initial hospital stay or leading to hospital re-admission within 90 days after surgery.
    - Time to (first) Re-hospitalisation within 90 days.
    - Functional status (assessed by Barthel Index by telephone questionnaire).
    - Health-related quality of life (assessed by EuroQoL EQ-5D and 12-item World Health Organisation Disability Assessment Schedule WHODAS 2.0) by telephone questionnaire).
    - Nutritional Risk Screening Score (NRS 2002)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 90 days after surgery
    - 1 year after surgery (occurrence of any individual component of the composite only)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    different transfusion strategies: LIBERAL vs. restrictive
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned15
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The trial formally starts with the registration of the first patient (FPI = first patient in), and the formal end of the study is the last 1 year after surgery visit of the last patient randomised (LPO = last patient out).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months100
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months100
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2470
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    These patients are tendentiously more seriously ill and would benefit from increased Hb
    If they would be excluded, results are no further more representative for geriatric patients, transfusion strategy remains unclear in this high risk population
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2470
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will be treated as usual after the individual treatment period of the clinical trial.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-09-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-30
    P. End of Trial
    P.End of Trial StatusOngoing
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